Quinuclidine analogs of sulpiride were prepared and studied by Mikhlina, E. E. et al as reported in Khim-Farmatsevt, Zh. 10, No. 11, 56-60 (1976); C.A. 86: 155489r exemplified by the compound: 5-aminosulfonyl-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-methoxybenzamide. The above named compound was reported in USSR Pat. No. SU-414-261 to have neuroleptic activity.
Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-benzamide and N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. et al in Khim-Farmatsevt. Zh 7, 20-24 (1974); C.A. 79: 146358a and the latter in Khim. Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); C.A. 65: 2220b. The compounds were reported to exhibit hypotensive, narcotic and ganglionic stimulation and blocking activities, properties not seen in the compounds of the present invention.
Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamid e was reported in Ger. Offen. No. 2,548,968; C.A. 87: 68001c and equivalently related U.S. Pat. No. 4,093,734 from 4-amino-3-chloro-5-trifluoromethylbenzoic acid chloride and 3-aminoquinuclidine. The compound is in a class among pyrrolidinyl and piperidinyl benzamides which are said to be useful as anxiolytics, anticonvulsives, antiemetics and antiulcerogenics.
G.B. 2,160,871A describes ether and thioether benzamide derivatives of dialkylaminoalkylamine or 1-alkyl-4-aminopiperidines that are useful in the treatment of emesis, and also the treatment of impaired gastric motility disorders. The patent compounds are analogs of metoclopramide and clebropride.
U.S. Pat. Nos. 4,593,034; 4,657,911; and 4,717,563 describe benzamide derivatives of 1-azabicyclo-[2.2.2]octan-3-amine (3-aminoquinuclidine) and benzoate derivatives of 1-azabicyclo[2.2.2]octan-3-ol (3-quinuclidinol) which exhibit gastric prokinetic and antiemetic effects in warm blooded animals.
U.S. Pat. Nos. 4,722,834 and 4,820,715 describe 3-quinuclidinyl benzamides which are useful for the control of emesis caused by administration of anticancer drugs to warm blooded animals.
European patent applications 200-444; 235-878; 214-772; and 254-854; and British patent applications 2152049 and 2125398 describe novel quinuclidine derivatives which exhibit serotonin antagonist activities, and are indicated for the treatment of pain and/or CNS disorders in warm blooded animals.
European patent application 306-345 describes 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides having antischizophrenic activity.
There is continuing interest in the development of quinuclidine derivatives which exhibit a novel combination of therapeutic properties for the treatment of disorders in warm blooded animals, with minimal neuropharmacological side effects.
Accordingly, it is an object of this invention to provide pharmaceutical compositions containing a therapeutical dosage of a N-(3-quinuclidinyl)-2-hydroxybenzamide or thiobenzamide which exhibit 5-HT(serotonin) modulating effects in warm blooded animals. The acidic phenolic group at the 2-position on the benzamide moiety has not previously been disclosed for compounds exhibiting central nervous system or serotonin modulating activity.
It is another object of this invention to provide a method for the treatment of warm blooded animals for anxiety or psychosis or other CNS disorders by mechanisms that do not involve dopamine receptor blockade.
It is another object of this invention to provide a method for the treatment of warm blooded animals for the improvement of cognition function.
It is a further object of this invention to provide a method for the treatment of warm blooded animals to alleviate migraine, cluster headache or trigeminal neuralgia symptoms.
Other objects and advantages of the present invention shall become apparent from the accompanying description and examples.